Anxiolytics. Benzodiazepine derivatives
ATC code: N05BA01 (Diazepam)
Brand names
Valium, Diastat, Valtoco, Diazepam Intensol
Allosteric GABA-A receptor modulator: enhances inhibitory GABA action. Anxiolytic, anticonvulsant, muscle relaxant, sedative. black box warning on respiratory depression and death when combined with opioids.
First line
Long-acting benzodiazepines (diazepam, chlordiazepoxide) are first-line for alcohol withdrawal management, prevention of delirium and seizures. Symptom-triggered dosing by CIWA-Ar: if score >8, give 10–20 mg diazepam orally or intravenously, repeat every 1–2 hours until sedation and CIWA-Ar reduction.
In severe hepatic impairment, lorazepam or oxazepam without active metabolites are preferred.
First line
Intravenous (0.15–0.2 mg/kg, max 10 mg) or rectal diazepam is one of the first-line agents for status epilepticus in adults and children per 2016. Lorazepam and midazolam are comparable in efficacy. Used immediately after a prolonged seizure (>5 minutes). If seizures persist 5 minutes after the first dose, repeat or move to second-line agents (fosphenytoin, valproate, levetiracetam).
In children, rectal diazepam (Diastat) is preferred when intravenous access is unavailable in the prehospital setting.
Sources
Second line
Benzodiazepines are used for short-term relief of acute anxiety or panic attacks, limited to 2–4 weeks. CG113 and Russian clinical guidelines emphasize avoiding long-term use due to dependence and tolerance risk. First-line drugs for anxiety disorders are SSRIs and SNRIs combined with CBT.
Avoid in patients with a history of substance use disorder. In elderly contraindicated per Beers Criteria 2023: risk of falls, fractures, and confusion.
Adjunct
Diazepam is used as a muscle relaxant for central spasticity (MS, spinal cord injury) and painful muscle spasms. Efficacy demonstrated in small RCTs. Modern practice prefers baclofen and tizanidine due to less sedation and lower dependence risk.
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Benzodiazepines are not standard therapy for chronic anxiety and insomnia. CG113, , and Russian guidelines limit benzodiazepine courses to 2–4 weeks. Long-term use causes tolerance, physical dependence, and cognitive impairment. Discontinuation produces withdrawal with anxiety, insomnia, and seizure risk.
Not recommended
In elderly patients with dementia, benzodiazepines are not used for behavioral disturbance. Beers Criteria 2023 lists benzodiazepines as potentially inappropriate in older adults: increased risk of falls, hip fractures, delirium, and paradoxical aggression. Preferred options are non-pharmacological strategies and, if necessary, low-dose atypical antipsychotics.
Additive CNS depression and respiratory depression. Alcohol increases fatal benzodiazepine overdose risk. Full alcohol abstinence required; if not feasible – switch to another anxiolytic class.
Source: FDA: Valium (diazepam) prescribing information (2021)
6 pairs found. Sorted from critical to minor.
Mechanism
Morphine and diazepam act on different receptors (μ-opioid and GABA-A) but both depress the central nervous system and the medullary respiratory centre. Effects are additive – risk of fatal respiratory depression rises several-fold. expanded the boxed warning to all opioid + benzodiazepine pairs in 2016.
Symptoms
Drowsiness, slowed and shallow breathing (respiratory rate below 12/min), cyanosis of lips and nail beds. Severe cases progress to respiratory arrest and death. Symptoms are easy to miss, so the patient and family are warned in advance.
Management
Avoid where possible. In palliative care and cancer pain, use minimal doses of both with continuous respiratory rate and saturation monitoring. Provide the patient and family with naloxone (opioid antidote) and train them in its use. Alternative anxiolytics without respiratory depression: gabapentin, pregabalin, hydroxyzine.
Sources
Mechanism
Tramadol is a weak opioid with additional serotonin–norepinephrine reuptake inhibition. With diazepam, the risk is doubled: additive CNS and respiratory depression plus a lowered seizure threshold (tramadol provokes seizures on its own).
Symptoms
Drowsiness, slowed breathing. Seizures may occur, especially in patients with prior epilepsy or with dose excess. Serotonin syndrome is less common unless other serotonergics are added.
Management
Avoid where possible. If unavoidable, minimal doses of both and a short course. Alternative analgesia: paracetamol with an NSAID; alternative anxiolytics: gabapentinoids or hydroxyzine.
Sources
Mechanism
Fluvoxamine blocks CYP2C19 and CYP3A4 – both diazepam metabolic routes. Diazepam plasma levels rise 2-fold, with stronger and longer effect.
Symptoms
Marked sedation, drowsiness, ataxia. In older patients: fall and fracture risk. Symptoms appear within 3–5 days.
Management
Halve the diazepam dose when combined. Alternative benzodiazepines without CYP dependence: lorazepam or oxazepam (glucuronidated). Alternative antidepressants without CYP2C19/CYP3A4 effect: sertraline or agomelatine.
Sources
Mechanism
Additive CNS depression and sedation. Older patients: delirium and fall risk.
Symptoms
Deep sedation, drowsiness, ataxia, confusion. Older patients: delirium and fall risk.
Management
Avoid the combination in older patients. If an anxiolytic is needed: minimum effective lorazepam or oxazepam dose (short-acting). For neuropathic pain, an alternative to amitriptyline: gabapentin or pregabalin.
Mechanism
Additive CNS depression and mild hypotension. Diazepam sedation may mask early symptoms of excessive blood pressure drop.
Symptoms
Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk. With additional antihypertensives: bradycardia (pulse below 60/min).
Management
The combination is acceptable for short diazepam use with pulse and blood pressure monitoring. In older patients: lorazepam or oxazepam at minimum doses (short-acting, less accumulation risk).
Mechanism
Loratadine rarely causes sedation at standard doses. With diazepam, mild additive CNS depression is possible, especially in older patients.
Symptoms
Sedation, fatigue, slowed reactions, impaired coordination. In older patients: fall and fracture risk. Driving and operating machinery: accident risk.
Management
On standard loratadine (10 mg/day) with intermittent diazepam (e.g. for anxiety), no adjustment needed. In older patients and on long-term benzodiazepine therapy, watch for sedation signs. For anxiety disorders, consider alternatives to diazepam: buspirone or CBT.
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Boxed warning
FDA boxed warning (2020): risk of respiratory depression, sedation, coma, and death when benzodiazepines are combined with opioids. Additional warning: risk of abuse, dependence, and withdrawal. Use the lowest effective dose for the shortest duration; taper gradually on discontinuation.
FDA category D. First-trimester use is associated with increased risk of cleft palate; third-trimester use with floppy infant syndrome and neonatal withdrawal. Prescribed only when benefit clearly outweighs risk, after obstetric consultation.
Passes into breast milk. Long-term use is discouraged due to accumulation in the infant (sedation, poor feeding). Single doses are acceptable with infant monitoring.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Diazepam is evaluated for the following indications with varying evidence strength: Alcohol withdrawal syndrome (evidence tier A), Status epilepticus (evidence tier A), Acute anxiety, short-term treatment (evidence tier B). See the full indication matrix with dosing and citations above on this page.
Common side effects of Diazepam (≥ 1 in 100): Sedation, drowsiness, fatigue, Ataxia, impaired coordination, Anterograde amnesia, Reduced attention, Muscle weakness. See the Safety section for uncommon and serious reactions.
FDA category D. FDA category D. First-trimester use is associated with increased risk of cleft palate; third-trimester use with floppy infant syndrome and neonatal withdrawal. Prescribed only when benefit clearly outweighs risk, after obstetric consultation.
Passes into breast milk. Long-term use is discouraged due to accumulation in the infant (sedation, poor feeding). Single doses are acceptable with infant monitoring.
Diazepam is contraindicated in: Hypersensitivity to benzodiazepines; Acute angle-closure glaucoma; Myasthenia gravis; Severe respiratory insufficiency; Sleep apnea syndrome. Full list in the Safety section.
FDA boxed warning (2020): risk of respiratory depression, sedation, coma, and death when benzodiazepines are combined with opioids. Additional warning: risk of abuse, dependence, and withdrawal. Use the lowest effective dose for the shortest duration; taper gradually on discontinuation.
physical dependence develops after courses over 4 weeks. Abrupt discontinuation causes severe withdrawal, sometimes with seizures.
first-line therapy for chronic insomnia is CBT-I, not benzodiazepines. Long-term benzodiazepine use reduces sleep quality and causes daytime drowsiness.
reaction and concentration are impaired for 24–48 hours after a dose because active metabolites have a long half-life.